We have shown that retroviral transactivating proteins can modulate in vitro cellular neuropeptide gene expression in rat c6 glioma cells. In addition, we have advanced in vivo data that retroviral transactivating proteins also modulate the expression of neuropeptide gene expression in the circulating lymphocytes of patients with the slow neurological disorder, tropical spastic parapesis. These data suggest a potential mechanism for the role of retroviral transacting proteins in the pathobiology of HTLV-1 related disorders such as TSP. We have also identified an animal model illustrating that a defect in the responsiveness of the CRH neuron to inflammatory mediators and a variety of neurotransmitters confers susceptibility to inflammatory disease and abnormal behavioral responsiveness to stress. Our data that enkephalin inhibits the synthesis and release of CRH, while retroviral transactivating factors markedly enhance the expression of the pro-enkephalin gene, suggest a novel model for the putative role of retroviruses in the pathogenesis of autoimmune arthritis, other inflammatory illnesses, and diseases characterized both by inflammation and atypical depression. Viral transactivation of neuropeptide gene expression could also potentially serve as a molecular bias for bidirectional communication between the immune and nervous system. We have been successful in identifying retinoic acid and leukotrienes as two novel regulators of pro-enkephalin gene transcription in amacrine neurons. This will help further in-depth characterization of cis and transacting factors for enkephalin and CRH gene expression in retinal amacrine neurons. We have also pioneered in showing synergism between cAMP and glucocorticoids in transcriptionally regulating neuropeptide (pro-enkephalin) gene expression through promotor sequences other than the classic GRE and CRE. Our data show that intronic sequences not otherwise utilized in promoting the expression of pro-enkephalin genes in somatic cells are essential for the expression of this gene in germ line cells (testicular). Only four other genes have previously been shown to possess germ-line specific expression-conferring promotor sequences that are distinct from the conventional upstream gene promotors, while this is the first demonstration for a neuropeptide gene.